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Tumor Lysis Syndrome: Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in patients treated with VENCLEXTA [see Clinical Trials Experience under Adverse Reactions].
VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS at initiation and during the ramp-up phase in all patients, and during reinitiation after dosage interruption in patients with CLL. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase. TLS, including fatal cases, has been reported after a single 20 mg dose of VENCLEXTA.
In patients with CLL who followed the current (5-week) dose ramp-up and the TLS prophylaxis and monitoring measures, the rate of TLS was 2% in the VENCLEXTA CLL monotherapy trials. The rate of TLS remained consistent with VENCLEXTA in combination with obinutuzumab or rituximab. With a 2- to 3-week dose ramp-up and higher starting dose in patients with CLL, the TLS rate was 13% and included deaths and renal failure [see Clinical Trials Experience under Adverse Reactions].
In patients with AML who followed the current 3-day ramp-up dosing schedule and the TLS prophylaxis and monitoring measures, the rate of TLS was 1.1% in patients who received VENCLEXTA in combination with azacitidine (VIALE-A). In patients with AML who followed a 4-day ramp-up dosing schedule and the TLS prophylaxis and monitoring measures, the rate of TLS was 5.6% and included deaths and renal failure in patients who received VENCLEXTA in combination with low-dose cytarabine (VIALE-C) [see Clinical Trials Experience under Adverse Reactions].
The risk of TLS is a continuum based on multiple factors, particularly reduced renal function, tumor burden, and type of malignancy. Splenomegaly may also increase the risk of TLS in patients with CLL.
Assess all patients for risk and provide appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities promptly. Employ more intensive measures (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases. Interrupt dosing if needed; when restarting VENCLEXTA, follow dose modification guidance [see Renal Impairment as follows; Important Safety Information, Recommended Dosage for Chronic Lymphocytic Leukemia, Recommended Dosage for Acute Myeloid Leukemia, and Risk Assessment and Prophylaxis for Tumor Lysis Syndrome under Dosage & Administration].
Concomitant use of VENCLEXTA with P-gp inhibitors or strong or moderate CYP3A inhibitors increases venetoclax exposure, which may increase the risk of TLS at initiation and during the ramp-up phase of VENCLEXTA. For patients with CLL, coadministration of VENCLEXTA with strong CYP3A inhibitors at initiation and during the 5-week ramp-up phase is contraindicated [see Contraindications]. For patients with AML, reduce the dose of VENCLEXTA when coadministered with strong CYP3A inhibitors at initiation and during the 3- or 4-day ramp-up phase. For patients with CLL or AML, reduce the dose of VENCLEXTA when coadministered with moderate CYP3A4 inhibitors or P-gp inhibitors [see Dosage Modifications for Drug Interactions under Dosage & Administration; Effects of Other Drugs on VENCLEXTA under Interactions].
Neutropenia: In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients when treated with VENCLEXTA in combination and monotherapy studies. Febrile neutropenia occurred in 4% to 6% of patients [see Clinical Trials Experience under Adverse Reactions].
In patients with AML, baseline neutrophil counts worsened in 95% to 100% of patients treated with VENCLEXTA in combination with azacitidine, decitabine, or low-dose cytarabine. Neutropenia can recur with subsequent cycles.
Monitor complete blood counts throughout the treatment period. For interruption and dose resumption of VENCLEXTA for severe neutropenia, see Table 16 for CLL and Table 18 for AML [see Dosage Modifications for Adverse Reactions under Dosage & Administration]. Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF).
Infections: Fatal and serious infections, such as pneumonia and sepsis, have occurred in patients treated with VENCLEXTA [see Clinical Trials Experience under Adverse Reactions].
Monitor patients for signs and symptoms of infection and treat promptly. Withhold VENCLEXTA for Grade 3 and 4 infection until resolution. For dose resumptions, see Table 16 for CLL and Table 18 for AML [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Immunization: Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery occurs. The safety and efficacy of immunization with live attenuated vaccines during or following VENCLEXTA therapy have not been studied. Advise patients that vaccinations may be less effective.
Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. In an embryo-fetal study conducted in mice, administration of venetoclax to pregnant animals at exposures equivalent to that observed in patients at a dose of 400 mg daily resulted in post-implantation loss and decreased fetal weight.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for at least 30 days after the last dose [see Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation].
Increased Mortality in Patients with Multiple Myeloma when VENCLEXTA is Added to Bortezomib and Dexamethasone: In a randomized trial (BELLINI; NCT02755597) in patients with relapsed or refractory multiple myeloma, the addition of VENCLEXTA to bortezomib plus dexamethasone, a use for which VENCLEXTA is not indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with VENCLEXTA in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials.
Renal Impairment: Due to the increased risk of TLS, patients with reduced renal function (CLcr <80 mL/min, calculated by Cockcroft-Gault formula) require more intensive prophylaxis and monitoring to reduce the risk of TLS when initiating treatment with VENCLEXTA [see Tumor Lysis Syndrome as previously mentioned; Important Safety Information, Recommended Dosage for Chronic Lymphocytic Leukemia, Recommended Dosage for Acute Myeloid Leukemia, and Risk Assessment and Prophylaxis for Tumor Lysis Syndrome under Dosage & Administration].
No dose adjustment is recommended for patients with mild, moderate or severe renal impairment (CLcr ≥15 mL/min) [see Pharmacology: Pharmacokinetics under Actions].
Hepatic Impairment: No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.
Reduce the dose of VENCLEXTA for patients with severe hepatic impairment (Child-Pugh C); monitor these patients more frequently for adverse reactions [see Dosage Modifications for Adverse Reactions and Dosage Modifications for Patients with Severe Hepatic Impairment under Dosage & Administration; Pharmacology: Pharmacokinetics under Actions].
Use in Children: The safety and effectiveness of VENCLEXTA have not been established in pediatric patients.
Juvenile Animal Toxicity Data: In a juvenile toxicology study, mice were administered venetoclax at 10, 30, or 100 mg/kg/day by oral gavage from 7 to 60 days of age. Clinical signs of toxicity included decreased activity, dehydration, skin pallor, and hunched posture at ≥30 mg/kg/day. In addition, mortality and body weight effects occurred at 100 mg/kg/day. Other venetoclax-related effects were reversible decreases in lymphocytes at ≥10 mg/kg/day; a dose of 10 mg/kg/day is approximately 0.06 times the clinical dose of 400 mg on a mg/m2 basis for a 20 kg child.
Use in the Elderly: Chronic Lymphocytic Leukemia: Of the 352 patients with previously treated CLL evaluated for safety from 3 open-label trials of VENCLEXTA monotherapy, 57% (201/352) were ≥65 years of age and 18% (62/352) were ≥75 years of age. No clinically meaningful differences in safety and effectiveness were observed between older and younger patients in the combination and monotherapy studies.
Acute Myeloid Leukemia: Of the 283 patients who received VENCLEXTA with azacitidine in VIALE-A, 96% were ≥65 years of age and 60% were ≥75 years of age.
Of the 13 patients who received VENCLEXTA in combination with decitabine in M14-358, 100% were ≥65 years of age and 62% were ≥75 years of age.
Of the 142 patients who received VENCLEXTA in combination with low-dose cytarabine in VIALE-C, 92% were ≥65 years of age and 57% were ≥75 years of age.
Clinical studies of VENCLEXTA in patients with AML did not include sufficient numbers of younger adults to determine if patients 65 years of age and older respond differently from younger adults.
